Investigator-assessed Objective Response Rate Research Articles

Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study

BackgroundPatients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate...

Polatuzumab- Rituximab with or without Bendamustine As Second-Line Therapy for Relapsed Refractory Large B-Cell Lymphomas: Single Center Experience

Introduction: Polatuzumab-vedotin, a CD79 antibody drug conjugate, is approved in combination with bendamustine and rituximab (Pola-BR) in patients with relapsed or refractory (R/R) Large B-cell Lymphoma (LBCL) who have received at least 2 prior lines of therapy. However, the registrational phase Ib/II study by Dr. Sehn and colleagues (Sehn et al. J Clin Oncol 2019) included 11 patients treated with this regimen as second line (2L) therapy. Given these data, real world applications have included the use of 2L polatuzumab rituximab (Pola-R) combination, with or without bendamustine, either as stand-alone treatment or as a bridge to cellular therapy. Here, we sought to analyze institutional outcomes of LBCL patients treated with this regimen and to determine whether the pattern of failure to frontline chemoimmunotherapy (1L CIT) was associated with subsequent response to polatuzumab containing regimen. Methods: We retrospectively reviewed data on 22 patients who received Pola-R with or without bendamustine as 2L therapy for LBCL at Miami Cancer Institute as of January 31st, 2022. Response was assessed by investigators using the Lugano criteria (Cheson et al. J Clin Oncol 2014). Objective response rate (ORR) and complete response (CR) rates were compared between primary refractory (no CR to 1L CIT) and relapsed LBCL patients. Progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Baseline characteristics are summarized in Table 1. The median age was 73 years (range, 57 to 92). Seven (32%) patients were ≥80 years old. The majority of patients (54%) had de novo DLBCL and non-GCB (59%) cell of origin by Hans algorithm. The median number of polatuzumab cycles was 4 (range, 1 to 7 cycles). Pola-BR was initiated with full dose bendamustine for 14 (64%) patients. Bendamustine was omitted for 6 (27%) patients and 2 (9%) patients received both Pola-R and Pola-BR cycles. The investigator-assessed best ORR was 68% (95% confidence interval [CI], 48.7% to 87.6%). Fourteen (64%) patients achieved a CR. Of the 6 patients who received Pola-R, 67% achieved a CR. The ORR was 90% for patients with relapsed disease, and 40% for those with primary refractory disease (p=0.057). CR rates were significantly lower in patients with disease refractory to 1L CIT (p=0.019). Median follow-up was 11 months. Nine (41%) patients received cellular therapy after polatuzumab containing regimen. Of these, 4 patients received CD19 targeted CAR T-cell therapy, and 5 patients received high dose chemotherapy followed by autologous stem cell transplant (ASCT). Other subsequent therapies after polatuzumab were: tafasitamab plus lenalidomide (n=1), loncastuximab tesirine (n=1) and conventional salvage CIT (n=3). Median PFS and OS were not reached. The 1-year PFS and OS were 54.5% (95% CI, 32.1% to 76.9%) and 70.5% (95% CI, 47.6% to 93.4%), respectively. Progression free survival and overall survival estimates are shown in Figure 1. Conclusions: Polatuzumab-Rituximab with or without bendamustine is an effective salvage option for R/R LBCL patients in the second-line setting. Refractoriness to frontline CIT was associated with lower response to subsequent polatuzumab treatment. Patients treated with this regimen can be successfully bridged to cellular approaches as definitive therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive hairy cell leukemia

AbstractBRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

Zandelisib (ME-401) in Japanese patients with relapsed or refractory indolent non-Hodgkin’s lymphoma: an open-label, multicenter, dose-escalation phase 1 study

The selective phosphatidylinositol 3-kinase δ inhibitor zandelisib demonstrated favorable safety and efficacy [objective response rate (ORR) 79%] in patients with B-cell malignancies in a phase 1b study in the US and Switzerland. In this phase 1 dose-escalation study (NCT03985189), 9 Japanese patients with relapsed/refractory indolent non-Hodgkin’s lymphoma (R/R iNHL) received zandelisib on a continuous daily schedule (45 or 60 mg) until progressive disease/unacceptable toxicity. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached. At a median follow-up of 17.5 months, Grade ≥ 3 treatment-emergent adverse events that occurred in 2 or more patients were neutrophil count decreased (55.6%; 5/9) and diarrhea (33.3%; 3/9). Immune-related toxicities, including hepatobiliary disorder, aspartate/alanine aminotransferase increased, diarrhea/colitis, organizing pneumonia, stomatitis, and rash, led to zandelisib discontinuation in 4 patients. The investigator-assessed ORR, based on modified Lugano criteria, was 100%, including 2 complete responses (22.2%; in follicular lymphoma patients receiving 60 mg/day). Median duration of response, progression-free survival, and time to response were 7.9, 11.1, and 1.9 months, respectively. Zandelisib demonstrated a manageable safety profile at 60 mg, the recommended phase 2 dose (RP2D) in Japanese patients. The RP2D resulted in favorable pharmacokinetics and anti-tumor efficacy in Japanese patients with R/R iNHL.Trial registration. NCT03985189 (ClinicalTrials.gov).

Safety and efficacy of anlotinib in combination with standard chemotherapy as first-line treatment for extensive-stage small cell lung cancer: A multi-center, prospective study (ACTION-2)

IntroductionExtensive stage small cell lung cancer (ES-SCLC) is associated with poor prognosis. Recently, anlotinib has demonstrated significant clinical activity as a third-line or further on treatment. This study aimed to evaluate the safety and efficacy of a combination of anlotinib and platinum-etoposide as first-line treatment in patients with ES-SCLC. MethodsThe present multi-center, single-arm, prospective study (NCT04684017) was conducted at three Chinese sites, and included patients with asymptomatic metastasis in the central nervous system. Patients were treated with up to six cycles of chemotherapy comprising etoposide with either carboplatin or cisplatin on day 1 of each cycle. Anlotinib was administered orally once daily on days 1–14 per cycle. The primary end points of the study were safety and investigator assessed objective response rate (ORR). ResultsA total of 101 patients were screened from August 2018 to September 2021, of which 86 who had received at least one dose of the treatment were included in the formal analysis. The median follow-up duration was 27.9 months. Complete response and partial response were observed in 2 and 73 patients, respectively, with an ORR of 87.2 % and a disease control rate of 97.7 %. Progression-free survival (PFS) and overall survival (OS) events occurred in 78 and 47 patients, respectively. The median PFS and OS were 9.0 (95 % confidence interval [CI]: 7.5–10.5) and 19 (95 % CI: 16.7–21.3) months, respectively. The incidence of grade 3 or higher adverse events (AEs) was 58.1 % and 24 patients (27.9 %) experienced serious treatment-related AEs. No fatalities consequent to AEs were recorded. ConclusionGiven its promising efficacy, safety profile and durability, anlotinib combined with chemotherapy deserves further investigation as first-line anticancer therapy in ES-SCLC (NCT: 04684017).

1017P AdvanTIG-105: Phase Ib dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with metastatic squamous (sq) and non-squamous (non-sq) non-small cell lung cancer (NSCLC)

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor + an anti-programmed cell death protein 1 (PD-1) antibody is a promising combination which shows potent efficacy in solid tumors. AdvanTIG-105 is a Phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with metastatic unresectable solid tumors (NCT04047862). In the dose-escalation part, OCI + TIS was well tolerated, preliminary efficacy was observed, and the recommended Phase 2 dose (RP2D) of OCI 900 mg intravenous (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion (Cohorts 1 [C1] & 2 [C2]) of the AdvanTIG-105 study. Treatment-naïve adult pts with histologically/cytologically confirmed metastatic sq (C1) or non-sq with EGFR/ALK/ROS-1 wild-type tumors (C2) NSCLC were enrolled. Pts in C1 received the RP2D of OCI + TIS with paclitaxel/nab-paclitaxel + carboplatin and pts in C2 received the RP2D of OCI + TIS with pemetrexed + cisplatin/carboplatin, both until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included safety. As of March 18, 2022, 84 pts were enrolled (C1: n=41; C2: n=43). The median study follow-up was 17.7 weeks (range 1.1–42.6) in C1 and 15.0 weeks (3.0–51.1) in C2. Of the 76 efficacy-evaluable pts, the confirmed ORR in C1 was 45.9% (95% confidence interval [CI]: 0.3, 0.6) and 25.6% (95% CI: 0.1, 0.4) in C2. In total, 81 pts (96.4%) experienced ≥ 1 treatment-emergent adverse event (TEAE), and 48 pts (57.1%) had ≥ Grade 3 TEAEs. Serious TEAEs occurred in 26 pts (31.0%). The most common TEAEs were anemia (41.7%), neutrophil count decreased (33.3%), and white blood cell count decreased (33.3%). The RP2D of OCI 900 mg IV Q3W and TIS 200 mg IV Q3W + chemo was generally well tolerated and showed antitumor activity in pts with treatment-naïve metastatic sq/non-sq NSCLC. Prof. Y. Yu and Prof. D. Huang have contributed equally to the study.

463P Efficacy and safety of larotrectinib in a pooled analysis of patients (Pts) with tropomyosin receptor kinase (TRK) fusion cancer with an extended follow-up

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in multiple tumour types. Larotrectinib, a highly selective TRK inhibitor, demonstrated an investigator-assessed objective response rate (ORR) of 75% across 206 pts with non-central nervous system (CNS) primary, TRK fusion-positive cancers (Hong et al, ASCO 2021). To better determine outcomes in a more mature dataset with a longer follow-up, we report on the first 164 pts enrolled as of February 2019 with a data cut-off of July 2021. Data were pooled from three clinical trials (NCT02576431, NCT02122913, and NCT02637687) of larotrectinib-treated pts with non-CNS primary, TRK fusion cancer. ORR was assessed by independent review committee (IRC) per RECIST v1.1. A total of 164 pts were evaluable for efficacy by IRC. There were 17 different cancer types; the most common were soft tissue sarcoma (42%), thyroid (16%), salivary gland (13%), and lung (8%). Fifty-five (34%) pts were <18 years. Fourteen (9%) pts had CNS metastases at baseline. The overall best ORR was 74% (95% confidence interval [CI] 67–81): 50 (30%) complete response (CR), including 10 (6%) pathological CR, 72 (44%) partial response, 22 (13%) stable disease, 13 (8%) progressive disease and seven (4%) not determined. After longer follow-up, 17 pts (10%) had an improved best overall response over that from the July 2019 data cut. Median time to response was 1.8 months (range 0.9–16.2). Median duration of response was 34.5 months (95% CI 27.6–43.3); median follow-up was 34.1 months. Median progression-free survival was 32.0 months (95% CI 23.4–40.2); median follow-up was 35.8 months. Median overall survival (OS) was not reached; median follow-up was 38.0 months. The 48-month OS rate was 66% (95% CI 57–75). Treatment duration ranged from 0.1 to 67.9 months. Treatment-related adverse events (TRAEs) were mainly Grade 1–2; 32 (20%) pts had Grade 3–4 TRAEs. With an extended follow-up, larotrectinib demonstrated durable and deepening responses, extended survival benefit and a favourable safety profile. This highlights the importance of identifying NTRK gene fusions in cancer pts.

Pyrotinib combined with apatinib for targeting metastatic non-small cell lung cancer with HER2 alterations: a prospective, open-label, single-arm phase 2 study (PATHER2)

BackgroundAlthough targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients’ therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients.MethodsHER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR).ResultsBetween March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5–26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported.ConclusionsPyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients.Trial registrationChinese Clinical Trial Registry Identifier: ChiCTR1900021684.

Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis

ObjectiveOlaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non‑platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. MethodsIn this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. ResultsOf 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. ConclusionsOlaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies.

Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142

In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, etal. Nivolumabplus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. Patients received nivolumab (3 mg/kg)plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals.

S256: TABELECLEUCEL FOR EBV-DRIVEN POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE FOLLOWING ALLOGENEIC HEMATOPOIETIC CELL OR SOLID ORGAN TRANSPLANT AFTER FAILURE OF RITUXIMAB ± CHEMOTHERAPY (ALLELE)

Background: Tabelecleucel is an investigational, off-the-shelf, allogeneic Epstein–Barr Virus (EBV)-specific T-cell immunotherapy being explored in patients (pts) with EBV-driven post-transplant lymphoproliferative disease (EBV+ PTLD). Median overall survival (OS) after rituximab (R) ± chemotherapy (C) failure is 0.7 months in EBV+ PTLD post allogeneic hematopoietic cell transplant (HCT) (Sanz ASH 2021) and 4.1 months post solid organ transplant (SOT) after R+C failure (Dharnidharka ASH 2021), demonstrating an urgent need for therapies in this ultra-rare disease. Tabelecleucel has shown promising outcomes (Prockop JCI 2020). Additionally, an investigator-assessed objective response rate (ORR) of >60% with >80% 2-year OS (Prockop EBMT 2021, Prockop ATC 2021, Prockop ASH 2021) was seen in pts with relapsed/refractory (R/R) EBV+ PTLD, with either complete or partial response to tabelecleucel. Safety data in >180 pts with tabelecleucel treated EBV+ PTLD demonstrate tumor flare reaction (TFR) as the only identified risk (Atara Biotherapeutics, Data on file). Aims: Report data from the ongoing Phase 3 ALLELE study (NCT03394365). Methods: ALLELE is a multicenter, open-label study investigating tabelecleucel in pts with EBV+ PTLD post HCT after R failure (n=33) and post SOT after R±C failure (n=33). Pts receive tabelecleucel at 2 x 106 cells/kg on Days 1, 8 and 15 in 35-day cycles. Response is evaluated by investigator and by independent oncologic response adjudication (IORA; primary assessment) using Lugano Classification with LYRIC modification. Efficacy endpoints include ORR, duration of response (DOR), time to response (TTR), and OS. Pts are assessed post treatment for up to 5 years for survival. Results: As of May 2021, 38 pts (14 HCT, 24 SOT) were evaluable by IORA and had the opportunity for 6 months follow-up. Median age was 52.9 (range, 3.2–81.5) years, 44.4%/47.2% of pts were high/intermediate risk per PTLD-adapted prognostic index, and median number of lines of prior systemic treatment was 1 (range, 1–5). R/R HCT and SOT pts received a median (range) of 3 (1–5) and 2 (1–6) cycles of tabelecleucel, respectively. ORR was 50.0% (19/38, 95% CI: 33.4, 66.6) overall, 50.0% (7/14, 95% CI: 23.0, 77.0) in HCT, and 50.0% (12/24, 95% CI: 29.1, 70.9) in SOT (Table). Overall, median TTR was 1.1 (0.7–4.7) months, 11 of 19 responders had DOR > 6 months, and median DOR was not reached (Table). Median OS was 18.4 (95% CI: 6.9, NR) months overall, not yet reached for HCT, and 16.4 (95% CI: 3.5, NR) months for SOT. 1-year survival rates were 61.1% (95% CI: 42.9, 75.0) overall, 66.8% (95% CI: 32.4, 86.6) for HCT, and 57.4% (95% CI: 35.2, 74.5) for SOT. Median OS was NR (95% CI: 16.4, NR) for responders and 5.7 (95% CI: 1.8, 12.1) months for non-responders. Responders had a higher 1-year survival rate vs non-responders: 89.2% (95% CI: 63.1, 97.2) vs 32.4% (95% CI: 12.1, 54.9) (Table). Serious treatment emergent AEs (TEAEs) and fatal TEAEs were reported in 57.1% and 7.1% of HCT and 62.5% and 16.7% of SOT pts respectively. No fatal TEAE was treatment related. There were no reports of TFR, infusion reactions, cytokine release syndrome, marrow rejection, or transmission of infectious diseases, and no events of graft vs host disease or organ rejection reported as related to tabelecleucel. Image:Summary/Conclusion: Tabelecleucel Phase 3 data show clinically meaningful outcomes and promising ORR and OS in a pt population with poor survival and no approved therapies. Tabelecleucel was well tolerated without evidence of safety concerns typically observed with other adoptive T-cell therapies.

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study

IntroductionBefotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. MethodsThis was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. ResultsA total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75–100 mg), respectively. At data cutoff (August 15, 2021), independent review committee–assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%–72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%–61.5%) in cohort A and 65.9% (95% CI: 60.1%–71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6–12.5) months in cohort A and 12.5 (95% CI: 11.1–13.8) months in cohort B. The median independent review committee–assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0–not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%–55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%–78.2%) and 55.9% (95% CI: 37.9%–72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6–NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8–NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. ConclusionsBefotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

Abstract 5180: A randomized, double-blind, placebo-controlled phase III study to evaluate AK104 plus platinum-containing chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer

Abstract Background: The current first-line standard of care for recurrent or metastatic cervical cancer is platinum-based doublet chemotherapy ± bevacizumab, but its efficacy is limited. Immunotherapies with programmed cell death receptor-1 (PD-1) inhibitor or combination of PD-1 and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors have been demonstrated to improve the clinical benefit for patients with recurrent or metastatic cervical cancer as second- or late-line treatment[1,2]. Their role in first-line treatment is under assessment. AK104 is a bispecific antibody (BsAb) that binds to both PD-1 and CTLA-4. This phase III trial aims to evaluate the efficacy and safety of AK104 plus standard chemotherapy with or without bevacizumab as first-line treatment for recurrent/metastatic cervical cancer. Trial Design: This phase III trial is a randomized, double-blind, placebo-controlled, multi-center study. Eligible patients are aged ≥ 18 and≤75 years, diagnosed with squamous cell carcinoma, adenocarcinoma or adenosquamous cell carcinoma of the cervix, not amenable to curative surgery or concurrent chemoradiotherapy, ECOG PS 0-1, and life expectancy ≥3 months. Patients will be excluded if they have prior systemic therapy for persistent, recurrent or metastatic disease, or have previously used anti-angiogenic therapy or immune therapy. Approximately 440 patients will be randomized (1:1) to AK104 + cisplatin/carboplatin+ paclitaxel± bevacizumab or placebo + cisplatin/carboplatin + paclitaxel ± bevacizumab. The treatment will be given every 3 weeks for up to 6 cycles, followed by maintenance therapy of AK104/placebo± bevacizumab until disease progression, intolerable toxicity, loss of clinical benefit as judged by the Investigator, withdrawal of consent, or completion of 2 years treatment of AK104/placebo. The primary endpoints are blinded independent central review (BICR)-assessed progression-free survival (PFS) and overall survival (OS). Second endpoints include Investigator-assessed PFS, BICR and Investigator-assessed Objective response rate (ORR), Disease control rate (DCR), Duration of response (DoR) and Time to response (TTR), and safety and tolerability for the treatment regime. The trial is currently enrolling patients. Clinical trial information: NCT04982237. Research Sponsor: Akeso Biopharma Co,. Ltd. Citation Format: Xiaohua Wu, Jing Wang, Yi Huang, Yuzhi Li, Yang Sun, Ke Wang, Michelle Xia, Baiyong Li, Wei Liu. A randomized, double-blind, placebo-controlled phase III study to evaluate AK104 plus platinum-containing chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5180.

Abstract CT032: Activity and safety of alectinib for ALK-altered solid tumors from MyPathway

Abstract Purpose: Alectinib is FDA-approved for ALK-positive, metastatic non-small cell lung cancer (NSCLC). We analyzed alectinib treatment in a pan-tumor population with ALK alterations from MyPathway (NCT02091141), a multi-basket study assessing approved therapies in non-indicated advanced solid tumors with relevant alterations. Methods: Enrolled patients (pts) were ≥18 yrs old and had metastatic tumors with ALK gene rearrangements, putative activating non-synonymous ALK mutations, and/or ALK gene amplification. Pts received alectinib 600 mg PO BID. The primary endpoint was investigator-assessed objective response rate (ORR; complete response [CR] + partial response [PR]). Other endpoints included duration of response (DOR), disease control rate (DCR; CR + PR + stable disease [SD] &amp;gt;4 mos), progression-free survival (PFS), and safety. Results: By the 11-18-2021 data cutoff, 21 pts with various tumor types had been enrolled and treated (ALK mutations or amplification, n=11 [52.4%]; ALK rearrangements +/- other ALK alterations, n=10 [47.6%]). Pts had a median of 2 (range, 1-5) prior lines of therapy. In the 10 pts with ALK rearrangements, there were 3 PRs (30.0%) with a median DOR of 6.8 mos (Table). An additional 3 pts in this group had SD &amp;gt;4 mos; DCR was 60.0% (6/10). In contrast, there were no responses among the 11 pts with ALK mutations or amplification. Confirmed ORR for the entire group was 14.3% (3/21), and DCR was 42.9% (9/21). Median PFS was 8.2 mos in pts with ALK rearrangements vs 1.8 mos for those with other ALK alterations. Alectinib-related adverse events (AEs) were observed in 85.7% of pts, with 3 (14.3%) experiencing grade 3 AEs (anemia; hypokalemia; and changes in AST, ALT, and/or blood creatinine levels). AEs were consistent with the known alectinib safety profile. Conclusions: Although the number of pts is small, alectinib appears active in those with non-NSCLC advanced solid tumors with ALK rearrangements. As in NSCLC, cancers with ALK mutations or amplification were not responsive to ALK inhibition. Table. Clinical outcomes Clinical Response Rearrangement (n=10) Mutation (n=7) Amplification (n=4) Median PFS, mos (all alterations) n Indications n Indications n Indications PR 3a Melanoma, Papillary urothelial carcinoma, Colon adenocarcinoma 0 NA 0 NA 9.3 SD &amp;gt;4 mos 3b,c Colon adenocarcinoma, Uterine leiomyosarcoma, Pancreatic adenocarcinoma 2 Squamous cell carcinoma, Soft tissue sarcoma 1 Uterine body clear cell carcinoma 5.7 SD ≤4 mos 0 NA 1 Fallopian tube serous carcinoma 0 NA PD 3d,e Colon adenocarcinoma, Esophageal adenocarcinoma, Uterine serous carcinoma 4 Anaplastic thyroid carcinoma, Esophageal adenocarcinoma, Colon adenocarcinoma (2) 3 Ovarian serous carcinoma, Gastric squamous cell carcinoma, Peritoneal non-small cell carcinoma 1.7 Non-evaluable 1f Uterine inflammatory myofibroblastic tumor 0 NA 0 NA NA aFusion gene partners: EMILIN1, DCTN1, and DIAPH2. bOne pt with ALK rearrangement and SD &amp;gt;4 mos also had ALK amplification. cFusion gene partners: STRN, IGFBP5, and EML4. dPts with ALK rearrangement and PD also had an ALK mutation (n=1) or ALK amplification (n=1). eFusion gene partner: STRN; fusion genes unknown for 2 pts. fPt withdrew prior to clinical assessment and was censored for PFS at 0.03 mos. NA, not applicable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. Citation Format: Charles Swanton, Claire F. Friedman, Christopher J. Sweeney, Funda Meric-Bernstam, David Spigel, Ron Bose, Howard Burris, Walter C. Darbonne, Julia Malato, Jonathan Levy, Yong Wang, Tania Szado, Katja Schulze, John Hainsworth, Razelle Kurzrock. Activity and safety of alectinib for ALK-altered solid tumors from MyPathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT032.

Abstract CT124: NeoCOAST-2: a randomized, open-label, phase 2 study of neoadjuvant durvalumab plus novel immunotherapies and chemotherapy (CT) followed by adjuvant durvalumab plus novel agents, in patients with resectable non-small-cell lung cancer (NSCLC)

Abstract Background: Neoadjuvant and adjuvant platinum-based CT improve survival rates in patients with resectable, early-stage NSCLC vs surgery alone. PD-1/PD-L1 inhibitors have shown clinical efficacy in patients with resectable, early-stage NSCLC, in both the neoadjuvant and adjuvant settings. The anti-PD-L1 monoclonal antibody (mAb) durvalumab, in combination with either the anti-CD73 mAb oleclumab or the anti-NKG2A mAb monalizumab, improved response rates and progression-free survival in patients with unresectable, Stage III NSCLC in the phase 2 COAST trial (NCT03822351). The NeoCOAST trial (NCT03794544) is currently evaluating the combination of durvalumab with oleclumab or monalizumab as neoadjuvant treatment in patients with resectable, early-stage NSCLC. NeoCOAST-2 (NCT05061550) is a multicenter study of neoadjuvant durvalumab combined with CT and either oleclumab or monalizumab, followed by surgery and adjuvant durvalumab plus oleclumab or monalizumab, in patients with resectable, Stage IIA-IIIA NSCLC. Methods: Eligible patients must have previously untreated, histologically/cytologically confirmed NSCLC, a WHO/ECOG performance status of 0 or 1, and life expectancy of ≥12 weeks. Patients must have tumor samples available for biomarker analyses, have planned surgery consisting of lobectomy, sleeve resection, or bilobectomy, and have a pre- or post-bronchodilator FEV1 of 1.0 L and DLCO &amp;gt;40% postoperative predictive value. Patients with sensitizing EGFR mutations or ALK translocations, history of allogeneic organ transplantation, active or prior documented autoimmune or inflammatory disorders, or uncontrolled intercurrent illness, are excluded. Approximately 140 patients will be randomized 1:1, stratified by PD-L1 expression (&amp;lt;1% vs ≥1%), to receive IV durvalumab + oleclumab or monalizumab + CT Q3W for 4 cycles prior to surgery, followed by durvalumab + oleclumab or monalizumab Q4W post surgery. Surgery must occur within 40 days of the last dose of neoadjuvant therapy. Patients will receive adjuvant therapy starting within 10 weeks after surgery, for 12 cycles or until disease progression (per RECIST v1.1). The primary endpoints are pathological complete response rate per blinded independent pathologist review, and safety and tolerability. Secondary endpoints include investigator-assessed event-free survival and disease-free survival, feasibility of planned surgery, major pathological response rate, changes in circulating tumor DNA, investigator-assessed objective response rate following neoadjuvant therapy, overall survival, pharmacokinetics and immunogenicity. Citation Format: Tina Cascone, Alexander Spira, Rosario G. Campelo, Dong-Wan Kim, Oday Hamid, Yee Soo-Hoo, Rakesh Kumar, Italia Grenga, Patrick Forde. NeoCOAST-2: a randomized, open-label, phase 2 study of neoadjuvant durvalumab plus novel immunotherapies and chemotherapy (CT) followed by adjuvant durvalumab plus novel agents, in patients with resectable non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT124.

Updated efficacy and safety results from the phase 2 study of serplulimab, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors.

2592 Background: Serplulimab is a novel humanized monoclonal antibody against PD-1. At ASCO 2021, we have presented the results from the phase 2 serplulimab study (NCT03941574) in patients with unresectable/metastatic microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) solid tumors who have progressed on or been intolerant to standard therapies with a median follow-up of 7.7 months. Here, we report the updated efficacy and safety results together with the results from sensitivity analysis after another 6-month follow-up. Methods: In this single-arm, open-label, multicenter, phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors were enrolled to receive 3 mg/kg of intravenous serplulimab every two weeks for up to two years. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per RECIST v1.1. Secondary endpoints included ORR assessed by the investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 10, 2021, 108 patients had received at least one dose of study treatment and were included in the safety set (SS). Among them, 68 patients with confirmed MSI-H (by local sites or central lab) were included in the main efficacy analysis population (MEAP); 58 patients with confirmed MSI-H (by central lab) and had no major protocol deviations were included in the sensitivity analysis population (SAP). The median follow-up duration was 13.5 months in the MEAP and 14.0 months in the SAP. IRRC-assessed ORR per RECIST v1.1 was 39.7% (95% CI 28.0–52.3; 3 complete response [CR]) in the MEAP and 43.1% (95% CI 30.2–56.8; 2 CR) in the SAP. Investigator-assessed ORRs were 38.2% (95% CI 26.7–50.8; 1 CR) and 41.4% (95% CI 28.6–55.1; 1 CR) in the MEAP and the SAP, respectively. Median DoR, PFS, and OS were not reached; 12-month OS rate was 74.5% (95% CI 62.2–83.3) in the MEAP and 82.4% (95% CI 69.7–90.1) in the SAP. In the SS, 57 (52.8%) patients had grade ≥3 treatment-emergent adverse events, most commonly anemia (9.3%). Thirteen (12.0%) patients had grade ≥3 immune-related adverse events. Three (2.8%) deaths (2 progressive disease and 1 intestinal obstruction) that might be related to serplulimab were reported. Conclusions: The encouraging antitumor activity and the manageable safety profile sustained after a longer duration of follow-up, supporting the further development of serplulimab as a potential tissue-agnostic antitumor treatment. Clinical trial information: NCT03941574.

A phase II study of alectinib in combination with bevacizumab as first-line treatment in advanced NSCLC with confirmed ALK fusion: ALEK-B trial.

9074 Background: Alectinib is one of the standard treatment options as an upfront therapy in advanced ALK-rearranged non-small-cell lung cancer. However, all patients will eventually progress to target therapy, developing resistance mechanisms. Preclinical data have demonstrated an enhanced activity combining an anti-vascular endothelial growth factor blockade to ALK tyrosine inhibitors. Hence, this study assesses the safety and efficacy of adding bevacizumab to alectinib. Methods: ALEK-B is an open-label phase II trial investigating the efficacy and safety of combined alectinib 600mg daily and bevacizumab 15mg/kg every three weeks in untreated patients with advanced ALK fusion-positive NSCLC. Every patient had confirmed molecular diagnosis by next-generation sequencing (Foundation One CDx) at baseline and progression. The primary endpoint was investigator progression-free survival (PFS). Secondary endpoints were investigator-assessed objective response rate (ORR), intracranial response (ICR), time to central nervous system (CNS) progression, and overall survival. Hence, we present the first interim analysis. Results: Between April 2020 and October 2021, 37 patients were recruited. At the data cut-off of January 31st, 2022, the median follow-up was 15.6 months (IQR 12.5), and an event of disease progression or death occurred in 1 of 36 patients (2.7%). The 12-month event-free survival rate was 97.1% (95% CI 91 to 99), and median PFS was not reached (95% IC 8.9 to NR). Of 36 evaluable patients, 35 had an objective response [ORR 97.2% (95% CI 91 to 99)], and 3 (8.3%) experienced a complete response. Five patients had brain metastases at baseline; among those with measurable disease (n = 4), the ICR was 100%, one complete response, and median duration of response of 11.4 months (IQR 13.1). The 12-month CNS event-free rate was 100%. Any grade adverse events occurred in 86.4% of patients; most common were AST/ALT increase (40.5%), diarrhea (32.4%), blood bilirubin increase (21.6%), anemia (18.9%), and peripheral edema (18.9%). Grade 1-2 hypertension and proteinuria occurred in five (13.5%) patients, and no &gt; G3 occurred. Grade ≥3 treatment-related AEs (TRAEs) occurred in 32.4%; most frequent were AST/ALT increase (27%) and creatinine increase (5.4%). Conclusions: The combination of Alectinib and bevacizumab demonstrated to be a safe and highly effective treatment in terms of response in the first-line setting. Moreover, it seems promising for patients with brain metastases. These results warrant the design of larger confirmatory trials, ideally a randomized phase III study. Clinical trial information: NCT03779191.

Phase II study of trastuzumab-pkrb and docetaxel anhydrous combination therapy in recurrent or metastatic salivary ductal carcinomas (KCSG HN18-08/KM11).

6018 Background: Salivary gland cancers (SGCs) are relatively rare, accounting for 1-6% of all neoplasms of the head and neck, have diverse disease course with respect to origin and pathology. Salivary duct carcinoma (SDC) is the most aggressive tumor subtype of primary SGC, showing high rates of local recurrence and distant metastases. In regard to previous studies which reported a high prevalence of HER2 positivity in SDCs, we conducted a single-arm, phase II study to evaluate the antitumor activity and safety of Herzuma (a trastuzumab biosimilar which demonstrated an equivalent efficacy to reference trastuzumab) in combination with docetaxel anhydrous (Nanoxel) in patients with HER2-positive advanced SDCs. Methods: Eligible patients had histologically confirmed HER2-positive (defined as IHC≥2+ and/or FISH HER2/CEN17 ratio ≥2.0) recurrent/metastatic SDC, or subtypes of SGC that were pathologically similar to SDC (excluding ACCs). They received Herzuma (8mg/kg i.v. loading dose, followed by 6mg/kg i.v.) and Nanoxel (75mg/m2 i.v.) every 3 weeks. The primary endpoint was the investigator-assessed objective response rate (ORR) according to RECIST v1.1. Secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. The calculated sample size was 43 patients for H1 of ORR ≥40%. Safety was evaluated by CTCAE v4.0. Results: A total of 43 patients were enrolled. Patient characteristics included: median age 60 (range 35–81); 86% male; 84% ECOG1; 84% SDC, 9% adenocarcinoma, 2% high grade mucoepidermoid carcinoma, and 5% other subtypes. Confirmed ORR was seen in 67% (95% CI, 52–81). No patient had a complete response as their BOR, 29 (67%) had a partial response, 11 (26%) had stable disease, 1 (2%) had progressive disease, and 2 (5%) were unevaluable. The DCR was 93% (95% CI, 81–99). The median PFS and OS were 8.2 months (95% CI, 6.7–9.7) and 23.3 months (95% CI, 19.9–26.7), respectively. Thirty-eight (88%) patients experienced a treatment-related AE (TRAE), with 15 (35%) patients experiencing ≥grade 3 TRAE including: neutropenia (10), febrile neutropenia (4), anemia (1), sepsis (1), anaphylaxis (1), decreased LVEF (1). There were no treatment-related deaths. Conclusions: The study met the primary endpoint of ORR. Herzuma and Nanoxel combination therapy demonstrated a promising treatment outcome in patients with HER2-positive recurrent/metastatic SDC. Clinical trial information: NCT03614364.

An investigator-initiated phase II trial of a PARP inhibitor niraparib monotherapy for patients with pre-treated, BRCA-mutated, unresectable/recurrent biliary tract, pancreatic, and other gastrointestinal cancers (NIR-B trial).

TPS4174 Background: Recent comprehensive genomic profiling tests have revealed therapeutic target molecules. However, because many targets are present in only a small fraction of patients, a large number of patients need to be screened for enrollment in a single study. In order to overcome this patient identification barrier, the SCRUM-Japan, nationwide large-scale genomic profiling platform, efficiently has been performed umbrella- and basket-type clinical trials. Among the platforms, we have reported that there are BRCA1/2-mutated patients in biliary tract, pancreatic, and other gastrointestinal cancers. Niraparib is an anticancer drug belonging to poly(ADP-ribose) polymerase (PARP) inhibitors. Niraparib has been shown to be selective for PARP1/2, to be more cytotoxic among other PARP inhibitor because of its PARP trapping activity. Methods: This is an investigator-initiated, multicenter, three-cohort phase 2 study. Main eligibility criteria are unresectable, advanced or recurrent biliary tract cancers (cohort A), pancreatic cancers (cohort B), and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline test or genomic profiling test with either circulating tumor DNA (ctDNA) or tumor tissue, refractory or intolerant to previous treatments, and adequate organ function. Primary endpoint is the investigator-assessed objective response rate in each cohort with a threshold-response rate of 10% and an expected response rate of 35%. Key secondary endpoints are progression-free survival, overall survival, disease control rate, duration of response, and safety. Patients with body weight of 77 kg or more and a platelet count of 150,000 /µL or more receive 300 mg of niraparib, and less than 77 kg or having a platelet count less than 150,000 /µL receive 200 mg of niraparib, orally once daily. Furthermore, pre-treatment tumor tissue and serial ctDNA will be collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. The trial was initiated in January 2021 with enrollment being ongoing. Thirty-three out of planned 60 patients (cohort A/B/C; 25/25/10, respectively) have been enrolled as of December 2021. Funding: Takeda Pharmaceutical Co., Ltd. Clinical trial information: jRCT2011200023.

KITE-363: A phase 1 study of an autologous anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (R/R) B-cell lymphoma (BCL).

TPS7579 Background: One mechanism by which B-cell tumors can resist the effects of CD19-targeted CAR T-cell therapy is through CD19 antigen escape (Neelapu et al. ASH 2019). Recent analyses in large B-cell lymphoma (LBCL) demonstrated that approximately one-third to two-thirds of relapses after infusion of CAR T-cell therapy were CD19 negative (Plaks et al. Blood. 2021; Spiegel, Dahiya et al. Blood. 2021; Spiegel et al. Nat Med. 2021). KITE-363 is an autologous CAR T cell transduced with a bicistronic vector with resultant expression of a CD19 CAR with a CD28 costimulatory domain and a CD20 CAR with a 41BB costimulatory domain. In preclinical studies, KITE-363 recognized and eliminated tumor cells expressing CD19 and/or CD20. KITE-363 CAR T-cell therapy has the potential to rescue CD19-negative relapsing patients with BCL as well as prevent CD19 antigen escape by minimizing selective pressure through upfront therapeutic dual targeting. This Phase 1, first-in-human, open-label, multicenter study (NCT04989803) will evaluate the safety and preliminary efficacy of KITE-363 in patients with R/R BCL. Methods: The Phase 1 design includes a 3+3 dose-escalation portion (1A), with 5 planned CAR T-cell levels, and a dose expansion portion (1B). Patients may receive optional corticosteroid bridging therapy following leukapheresis. Patients will then receive conditioning chemotherapy (cyclophosphamide and fludarabine) on Day ‒5 to Day ‒3 followed by KITE-363 infusion on Day 0. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per Lugano criteria (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete response rate, time to next treatment, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells in blood and cytokines in serum. Eligible adult patients have histologically confirmed BCL, including LBCL, indolent non-Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma (HL), and BCL, unclassifiable (with features intermediate between diffuse LBCL and classical HL), that is R/R after ≥2 lines of therapy (patients with LBCL may have primary refractory disease). Other key inclusion criteria are adequate bone marrow and organ function and ECOG performance status 0‒1. Key exclusion criteria are central nervous system (CNS) involvement from lymphoma, active infection including hepatitis B and C, and clinically significant CNS disorder. This study is currently open and accruing patients. Clinical trial information: NCT04989803.